Multidimensional analysis of deubiquitinating enzymes in colorectal cancer: biological mechanisms and targeted therapeutic strategies.

Colorectal cancer (CRC) is one of the most common and deadly cancers worldwide. Its significant heterogeneity and cellular plasticity are key drivers of clinical treatment challenges and drug resistance. Deubiquitinating enzymes (DUBs) play a critical role in the mechanisms regulating the onset and progression of CRC. As key functional molecules of the ubiquitin-proteasome system (UPS), DUBs exert central influences on processes such as DNA damage response and repair, metabolic reprogramming, non-apoptotic cell death, and clinical treatment outcomes in CRC cells. This article systematically elucidates the key molecular mechanisms of DUBs in CRC from multiple perspectives, with a particular focus on their bridging role between intrinsic stress adaptation and tumor immune evasion in cancer cells. Furthermore, this article critically evaluates the evolution of DUB-targeting strategies, from the limitations of traditional small-molecule inhibitors to technological innovations such as protein degradation-targeting chimeric proteins (PROTACs) and deubiquitinase-targeting chimeric proteins (DUBTACs). These strategies aim to reverse multidrug resistance by degrading oncogenic DUBs or stabilizing tumor-suppressor proteins, thereby providing new research leads and potential translational directions for precision therapy in CRC.